Immunoproteasome Subunit LMP7 Deficiency and Inhibition Suppresses Th1 and Th17 but Enhances Regulatory T Cell Differentiation
Immunoproteasome Subunit LMP7 Deficiency and Inhibition Suppresses Th1 and Th17 but Enhances Regulatory T Cell Differentiation
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DOI：
10.4049/jimmunol.1201183
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发表时间：
2012-10-15
影响因子：
4.4
通讯作者：
Groettrup, Marcus
中科院分区：
文献类型：
--
作者：
Kalim, Khalid W.;Basler, Michael;Groettrup, Marcus
免疫蛋白酶体产生在MHC I类分子上呈递给细胞毒性T细胞的肽。ONX 0914（以前称为PR-957）是免疫蛋白酶体亚单位低分子量多肽（LMP）7（β 5i）的选择性抑制剂，可减缓糖尿病、结肠炎和关节炎小鼠模型的疾病进展。本研究的目的是研究LMP 7特异性抑制对参与体外和体内自身免疫性疾病进展的主要Th细胞分化途径的影响。我们在不同的Th细胞极化条件下使用了ONX 0914处理的野生型CD 4（+）T细胞和LMP 7（-/-）CD 4（+）T细胞，重点关注所涉及的效应细胞因子和转录因子，并将其与野生型CD 4（+）T细胞进行比较。使用葡聚糖硫酸钠诱导的结肠炎的小鼠模型和结肠炎的T细胞转移模型进行体内评估。LMP 7的缺失或抑制抑制了Th 17的产生，但促进了调节性T细胞（Treg）的发育。在发育中的Th 17细胞中，免疫蛋白酶体抑制剂阻断了STAT 3的磷酸化，而在THBE中，SMAD磷酸化增强。此外，LMP 7抑制导致STAT 1磷酸化和Th 1分化减少。这些发现在体内得到证实，因为在葡聚糖硫酸钠诱导的结肠炎中，LMP 7抑制或缺乏导致Th 1和Th 17扩增减少，同时促进Treg发育。此外，在结肠炎的T细胞依赖性转移模型中，LMP 7特异性抑制导致体内Th 1和Th 17分化减少。LMP 7通过影响分化期间受体近端信号的平衡来支配Th细胞谱系确定。这些数据使LMP 7成为治疗自身免疫性疾病的有希望的药物靶标。免疫学杂志，2012，189：4182-4193。
The immunoproteasome generates peptides presented on MHC class I molecules to cytotoxic T cells. ONX 0914 (formerly called PR-957) is a selective inhibitor of the immunoproteasome subunit low molecular mass polypeptide (LMP) 7 (beta 5i) that attenuates disease progression in mouse models of diabetes, colitis, and arthritis. The aim of this study was to investigate the effect of LMP7-specific inhibition on major Th cell differentiation pathways involved in the progression of autoimmune diseases in vitro and in vivo. We used ONX 0914-treated wild-type CD4(+) T cells and also LMP7(-/-) CD4(+) T cells under different Th cell-polarizing conditions, focusing on the effector cytokines and transcription factors involved, and compared them with wild-type CD4(+) T cells. Mouse models of dextran sodium sulfate-induced colitis and a T cell transfer model of colitis were used for in vivo assessment. Deletion or inhibition of LMP7 suppressed generation of Th17 but promoted regulatory T cell (Treg) development. In developing Th17 cells, immunoproteasome inhibition blocked phosphorylation of STAT3, whereas in Tregs, SMAD phosphorylation was enhanced. Additionally, LMP7 inhibition led to reduced STAT1 phosphorylation and Th1 differentiation. These findings were confirmed in vivo as LMP7 inhibition or deficiency resulted in reduced Th1 and Th17 expansion while promoting Treg development in dextran sodium sulfate-induced colitis. Also, in a T cell-dependent transfer model of colitis, LMP7-specific inhibition led to reduced Th1 and Th17 differentiation in vivo. LMP7 governs Th cell lineage determination by affecting the balance of receptor proximal signals during differentiation. These data render LMP7 a promising drug target for the treatment of autoimmune diseases. The Journal of Immunology, 2012, 189: 4182-4193.